Box 1a: Symbol key Symbol Explanation Symbol Explanation In vitro diagnostic medical device Content sufficient for < n > tests Lot number Date of manufacture YYYY-MM- (DD) Do not reuse Product code Consult instructions for use Use by YYYY-MM- (DD) Manufacturer Do not use if packaging is damaged Temperature limitation Lower limit of temperature Sterile Upper limit of temperature Irritant Biological risk Keep away from sunlight Keep dry Authorized representative in the European Community European Health & Safety Product Label 1
Box 1b: Globally harmonized system of classification and labeling of chemicals (hazard pictograms): New CLP symbols: (very) Toxic Dangerous for the environment Oxidizing Highly or extremely flammable Corrosive Explosive Replaces the harmful symbol: Refers to less serious health hazards such as skin irritancy / sensitisation NEW: Reflects serious longer term health hazards such as carcinogenicity and respiratory sensitisation 2
Box 2: Labeling legibility for in-vitro diagnostics RDT box labeling: [A] MINIMUM STANDARD: Based on EC guidelines for readability of labeling 1 (i.e. Characters of at least 7 points, or of a size where the lower case x is at least 1.4mm in height // space between lines of at least 3mm): This is an example of the minimum acceptable text size and spacing for labeling of medicinal products according to EC guidelines (to evaluate Malaria RDT box labeling) [B] RECOMMENDED STANDARDS: Example 1 (font and size) Based on the US FDA guidelines 2 (e.g. Serif font 12 points): This is the recommendation of FDA for text font and size of medical device labeling aimed at patients and lay caregivers (to evaluate Malaria RDT box labeling) Example 2 (size) Based on HarT guidelines (e.g. font size equivalent to Myriad bold 10): This is an example of recommended text size mentioned in the HarT guidelines (to evaluate Malaria RDT box labeling) IFU: MINIMUM STANDARD: Based on EC guidelines for readability of package leaflet 1 (i.e. At least type size of 9 points -as measured in font Times New Roman, not narrowed - with a space between lines of at least 3 mm): This is an example of the minimum acceptable text size and spacing for package leaflets according to EC guidelines (to evaluate Malaria RDT IFU readability) NOTE: It is important to choose a font in which similar letters/numbers, such as i, l and 1 can be easily distinguished from each other. Figure 1: Convention of terms for the front-view of a malaria RDT box. 1 http://ec.europa.eu/health/files/eudralex/vol2/c/2009_01_12_readability_guideline_final_en.pdf 2 http://www.fda.gov/regulatoryinformation/guidances/ucm070782.htm#c 3
Figure 2 - Example label on the top of the RDT box xx C x C Commercial name, Malaria Antigen Pf/Pan (HRP2 / pldh) RDT xxxxxxxxxx XX Rapid test for the antigen detection of malaria (Plasmodium x) Test rapide de détection d antigène du paludisme (Plasmodium x) Prueba rápida para detección de antígeno de malaria (Plasmodium x) Teste rápido para detecção de antígeno da malária (Plasmodium x) Professional-use only xxxxxxx YYYY-MM Name and physical address of legal manufacturer. Website and/or telephone and/or fax number. Blue color indicates RDT product specific items. Exception: custom/variable prints (e.g. lot number, expiration date) can be printed only in one side. Figure 3 Example labelling of one lateral side and the front of an RDT box 4
Commercial name, Malaria Antigen Pf/Pan (HRP2 / pldh) RDT xxxxxxxxxxx Content: Cassettes (XX) Specimen transfer devices (XX) Alcohol swabs (XX) Lancets (XX) Buffer bottle (XX) Instructions for use (XX) (XX) xxxxxxx [indicate symbol for method of sterilization] Required but not provided: Gloves Biosafety sharps container Biohazard waste container Timer Pencil / pen YYYY-MM x C xx C (XX) indicates Quantities: Number of items or Number of pouches (and what each pouch contains) Blue color indicates RDT product specific items. Exception: custom/variable prints (e.g. lot number, expiration date) can be printed only in one side. Figure 4 Example labeling of the cassette primary packaging 5
SIDE A xx C x C Commercial name, Malaria Antigen Pf/Pan (HRP2 / pldh) RDT For product code: XXXXXXX xx Content: - 1 cassette - 1 desiccant - 1 specimen transfer device Manufacturer Name or logo SIDE B xxxxxxx YYYY-MM Blue color indicates RDT product specific items. Figure 5 Conventions for terms of the cassette Distal 6
Long axis Supplemental document Round 7: Annex (AID) - HarT checklist Left Right Proximal Short axis Figure 6 Proposal for printing relevant information on the buffer bottle Commercial name, Malaria Antigen Pf/Pan (HRP2/ pldh) RDT For product code: XXXXXX Contents : Buffer xxxxxxx YYYY-MM x C xx C Manufacturer Name (or logo) XX ml or XX number of examinations Box 3: Test Principle (IFU) 7
The cassette contains a test strip pre-coated with capture antibodies. The sequence of events is as follows: (1) Whole blood is applied to the specimen well (labelled well 1). (2) Next, buffer is applied to the buffer well (labelled well 2). (3) Migration of the blood specimen/buffer mixture starts, towards the other end of the cassette. (4) The blood specimen-buffer mixture passes the conjugate pad, which contains detection antibodies targeting Pf-HRP2, Pf-pLDH, Pv-pLDH, pan-pldh and/or aldolase antigens. These detection antibodies are conjugated to colloidal gold. If present in the specimen, Plasmodium target antigens bind to this detection antibody-conjugate. (5) The antigen-antibody-conjugate complex migrates further and binds to the capture Plasmodium-specific antibodies present on the test line. These capture antibodies bind to another site (epitope) of the Plasmodium target antigens. (6) The capture antibodies are applied on a narrow section of the test strip: as a result, the antibody-conjugate with the colloidal gold will be concentrated and become visible as a red colored line. (7)The excess of the detection antibody-conjugate that was not bound by the Plasmodium target antigens and the capture antibodies moves further until it binds to a goat anti-mouse control antibody. There, the colloidal gold will create a red colored control line. The visualization of the control line indicates that the migration was successful. It does not confirm the presence of specimen. Table 1: Description of different result possibilities Lines that you see Record the following result Picture/Drawing NO line at C (= control) INVALID -Take a new cassette packaging and repeat the test! All possible line combinations* Line at C and NO other line NEGATIVE All possible line combinations* Line at C AND at Pf POSITIVE for Plasmodium falciparum All possible line combinations* Line at C, at Pf AND at pan Line at C AND at pan POSITIVE for Plasmodium falciparum (or rarely, a mixed infection with P. vivax, P. ovale and/or P. malariae) POSITIVE for non-falciparum malaria: P. vivax, P. ovale or P. malariae (or, rarely, a mixed infection with these species) All possible line combinations* All possible line combinations* Other line combinations Write down the result All possible line combinations* *See below examples for a 2-band, 3-band and 4-band test. A full Guide to interpretation of results for all RDT types is available in Annex 2 of WHO-FIND Product Testing reports: http://www.who.int/malaria/publications/atoz/9789241510035/en/ Guide to results of generic Pf malaria RDT: 8
9
Guide to results of generic pan Pf malaria RDT: 10
Guide to results of generic pan Pv Pf malaria RDT (I): 11
Guide to results of generic pan Pv Pf malaria RDT (II): 12